Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. The essential autophagy regulator beclinl is monoallelically deleted in breast cancers, but the mechanism of tumor suppression by autophagy is not known. We developed a new mouse model for breast cancer progression and applied it to the study of autophagy in mammary tumorigenesis. We found that autophagy mitigates metabolic stress and protects mammary cancer cells from genome damage and instability, likely thereby limiting tumorigenesis. I now propose to further characterize the role of autophagy in breast cancer. The specific aims of my proposal are: 1) to determine the mechanism by which deficient autophagy promotes genome damage in mouse mammary epithelial cells and to validate the identified mechanism in human breast cancer cell lines and tumors. The hypothesis is that autophagy defects compromise cellular metabolism under starvation resulting in DMA and likely also protein damage. DMA strand breaks and damaged protein accumulation will be compared in wild type and autophagy-deficient cells under metabolic stress in vitro and in tumors in vivo, and their underlying causes will be examined. 2) To determine the role of deficient autophagy in breast cancer progression. The hypothesis is that autophagy defects promote genomic instability and synergize with breast cancer promoting functions to accelerate cancer progression. To test this hypothesis, tumors generated by autophagy-deficient cells will be tested for genomic instability and activation of breast cancer promoting biological pathways. Also, beclinl mice will be crossed with mammary tumor-prone mice and tumorigenesis will be studied. 3) To determine whether deficient autophagy correlates with disease stage, treatment responsiveness and clinical outcome in breast cancer by using human breast cancer databases. The long-term objective of my proposal is to apply the knowledge obtained for the rational design of more efficacious treatments against breast cancer based on the functional status of important biological processes, such as autophagy. Relevance: The results of the proposed studies will provide novel insights into breast cancer pathogenesis and will hopefully contribute to the development of individualized and improved anticancer treatments. [unreadable] [unreadable] [unreadable] [unreadable]